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Characterization of mechanism involved in acquired resistance to sorafenib in a mouse renal cell cancer RenCa model

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Abstract

Purpose

The objective of this study was to investigate the mechanism mediating the acquisition of a resistant phenotype to sorafenib in renal cell carcinoma (RCC).

Methods

A parental mouse RCC cell line, RenCa (RenCa/P), was continuously exposed to increasing doses of sorafenib, and a cell line resistant to sorafenib (RenCa/R), showing an approximately sixfold higher IC50 than that of RenCa/P, was established. Changes in the expression of several molecules in these cell lines following sorafenib treatment were evaluated by western blotting, and the effects of sorafenib treatment on the in vivo growth patterns were compared.

Results

There were no significant differences in sensitivities to potential agents against RCC between RenCa/P and RenCa/R. Among several apoptosis-related proteins, the expression of clusterin in RenCa/R was significantly greater than that in RenCa/P. Following treatment with sorafenib, the expression level of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) in RenCa/P, but not that in RenCa/R, was significantly decreased. Furthermore, additional treatment with a specific inhibitor of the MAPK signaling pathway significantly increased the sensitivity of RenCa/R to sorafenib, but not that of RenCa/P. There was no significant difference between the in vivo growth patterns of RenCa/P and RenCa/R in mice without sorafenib treatment; however, the growth inhibitory effect of sorafenib on the RenCa/P tumor was significantly greater than that on the RenCa/R tumor.

Conclusions

These findings suggest that the upregulation of clusterin and continuous activation of the MAPK pathway during sorafenib treatment may be involved in the acquisition of a resistance to sorafenib in RCC.

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Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    K. Harada, H. Miyake, Y. Kusuda & M. Fujisawa

Authors
  1. K. Harada
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  2. H. Miyake
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  3. Y. Kusuda
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  4. M. Fujisawa
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Corresponding author

Correspondence to H. Miyake.

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Harada, K., Miyake, H., Kusuda, Y. et al. Characterization of mechanism involved in acquired resistance to sorafenib in a mouse renal cell cancer RenCa model. Clin Transl Oncol 16, 801–806 (2014). https://doi.org/10.1007/s12094-013-1151-9

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  • DOI: https://doi.org/10.1007/s12094-013-1151-9

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